What is it about?
Proteins can function when in their normal, soluble state, and cease to function when in any other state. The official narrative has been that when proteins become aggregated, they turn toxic. But a review of data in humans affected by Alzheimer's disease, the most common neurodegenerative disorder, the problem is that amyloid-beta, a key protein for normal brain health, depletes as it transforms into amyloid, cross-beta sheets of stable, non-functioning protein.
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Why is it important?
We reviewed data to show that the problem in neurodegeneration is the loss of normal protein rather than its accrual into "toxic proteinopathy." This opens a completely different therapeutic strategy: replacing normal protein to levels above a compensation threshold. This would represent a major departure from the decades-old approach to Alzheimer's and other neurodegenerative disorders, centered on anti-amyloid approaches, which have yielded futility or harm.
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This page is a summary of: Soluble Amyloid-β Consumption in Alzheimer’s Disease, Journal of Alzheimer s Disease, August 2021, IOS Press, DOI: 10.3233/jad-210415.
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Losing amyloid in Alzheimer's disease
Cognitive impairment could be due to a decline in soluble amyloid-beta peptide instead of the corresponding accumulation of amyloid plaques. To test this hypothesis, we analyzed the brain scans and spinal fluid from 600 individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative study, who all had amyloid plaques. From there, we compared the amount of plaques and levels of the peptide in the individuals with normal cognition to those with cognitive impairment. We found that, regardless of the amount of plaques in the brain, the individuals with high levels of the peptide were cognitively normal. Alzheimer’s disease symptoms seem, thus, dependent on the depletion of the normal protein, which is in a soluble state, instead of when it aggregates into plaques.
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